Abstract
It is well established that leptin increases the sensitivity of carbohydrate metabolism to the effects of insulin. Leptin and insulin also have potent effects on lipid metabolism. However, the effects of leptin on the regulation of liver lipid metabolism by insulin have not been investigated. The current study addressed the effects of leptin on insulin-regulated hepatic very low-density lipoprotein (VLDL) metabolism in vivo in rats. A 90-min hyperinsulinemic/euglycemic clamp (4 mU/kg x min(-1)) reduced plasma VLDL triglyceride (TG) by about 50% (P < 0.001 vs. saline control). Importantly, a leptin infusion (0.2 microg/kg x min(-1)) in combination with insulin reduced plasma VLDL-TG by about 80% (P < 0.001 vs. insulin alone). These effects did not require altered skeletal muscle lipoprotein lipase activity but did include differential effects of insulin and leptin on liver apolipoprotein (apo) B and TG metabolism. Thus, insulin decreased liver and plasma apoB100/B48 levels (approximately 50%, P < 0.01), increased liver TGs (approximately 20%, P < 0.05), and had no effect on fatty acid oxidation. Conversely, leptin decreased liver TGs (approximately 50%, P < 0.01) and increased fatty acid oxidation (approximately 50%, P < 0.01) but had no effects on liver or plasma apoB levels. Importantly, the TG-depleting and prooxidative effects of leptin were maintained in the presence of insulin. We conclude that leptin additively increases the suppressive effects of insulin on hepatic and systemic VLDL metabolism by stimulating depletion of liver TGs and increasing oxidative metabolism. The net effect of the combined actions of insulin and leptin is to decrease the production and TG content of VLDL particles.
Highlights
It is well established that leptin increases the sensitivity of carbohydrate metabolism to the effects of insulin
Fects involves complementary, but distinct, effects of insulin and leptin on liver apolipoprotein levels and oxidative metabolism, respectively; and 3) the TG-depleting and oxidative effects of leptin on lipid metabolism are maintained in the presence of insulin, a predominantly prolipogenic, antioxidative hormone
We have established in the current study that the combined actions of insulin and leptin on very low-density lipoprotein (VLDL) metabolism are greater the effects of either hormone alone
Summary
It is well established that leptin increases the sensitivity of carbohydrate metabolism to the effects of insulin. Insulin decreased liver and plasma apoB100/B48 levels (ϳ50%, P Ͻ 0.01), increased liver TGs (ϳ20%, P Ͻ 0.05), and had no effect on fatty acid oxidation. The effects of leptin are mediated by the stimulation of liver oxidative metabolism, an effect involving inactivation of acetyl CoA carboxylase (ACC), which results in a depletion of the liver TG pool available for incorporation into VLDL particles [5, 7]. Together these studies suggest that insulin and leptin may act in concert to regulate hepatic lipid metabolism. 2170 Huang et al Leptin, Insulin, and VLDL metabolism, respectively, and 3) the TG-depleting and oxidative effects of leptin on lipid metabolism are maintained in the presence of insulin
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